The present invention relates to the field of pharmaceutical technology and describes a novel administration form comprising an acid-labile active compound, in particular an acid-labile proton pump inhibitor. The novel administration form is suitable for oral administration. Furthermore, the invention also relates to a process for the production of the administration form and preparations which can be used for the production of the administration form.
It is generally known to coat oral administration forms, e.g. tablets or pellets, which contain an acid-labile active compound, with an enteric coating which is rapidly dissolved in the alkaline medium of the intestine after gastric passage. An example of such acid-labile active compounds is acid-labile proton pump inhibitors (H+/K+ ATPase inhibitors), in particular pyridin-2-ylmethylsulfinyl-1 H-benzimidazoles, such as are disclosed, for example, in EP-A-0 005 129, EP-A-0 166 287, EP-A-0 174 726 and EP-A-0 268 956. On account of their H+/K+ ATPase-inhibiting action, these are of great importance in the therapy of diseases which result from increased gastric acid secretion. Examples of already commercially available active compounds from this group are 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methylsulfinyl]-1H-benzimidazole (INN: omeprazole), 5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridinyl)-methylsulfinyl]-1H-benzimidazole (INN: pantoprazole), 2-[3-methyl-4-(2,2,2-trifluoroethoxy)2-pyridinyl)-methylsulfinyl]-1H-benzimidazole (INN: lansoprazole) and 2-{[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]-methylsulfinyl}1H-benzimidazole (INN: rabeprazole).
Because of their strong tendency to decompose in a neutral and, in particular, acidic environment, strongly colored decomposition products also being formed, it is also necessary in this case for oral preparations to protect the active compounds from the action of acids and moisture and destruction by undesired interaction with pharmaceutical auxiliaries. In the case of the highly acid-labile pyridin-2-ylmethylsulfinyl-1H-benzimidazoles, it is moreover necessary to process these in the tablet core or in pellets in the form of their alkaline salts, for example as sodium salts, or together with alkaline substances. Since the substances possible for enteric coatings are those having free carboxyl groups, a problem results that the enteric coating, because of the alkaline medium in the interior, begins to dissolve or is even dissolved from the inside out and the free carboxyl groups promote the decomposition of the active compounds. It is therefore necessary to provide an insulating intermediate layer (subcoating) between the enteric coating and the alkaline tablet core or pellet. In EP-A-0 244 380, it is proposed to coat cores which contain the active compound together with alkaline compounds or as an alkaline salt with at least one layer of nonacidic, inert pharmaceutically acceptable substances, which is soluble in water or rapidly disintegrates in water, before the enteric layer is applied. The intermediate layer or intermediate layers act as pH-buffering zones in which the hydrogen ions diffusing in from outside can react with the hydroxyl ions diffusing out of the alkaline core In order to increase the buffer capacity of the intermediate layer, it is proposed to incorporate buffer substances into the intermediate layer(s). In practice, it is possible by this process to obtain preparations which are stable to a certain extent. However, relatively thick intermediate layers are needed to avoid the unattractive discolorations which occur even in the case of only slight decomposition. Additionally, a considerable effort has to be made during preparation to avoid traces of moisture.
In EP-A-0 519 365, a formulation for the active compound pantoprazole on the principle of the alkaline core coated with a water-soluble intermediate layer and an enteric layer is proposed, in which an improved stability is achieved by use of polyvinylpyrrolidone and/or hydroxypropylmethylcellulose as a binder for the alkaline core.
In EP-A-0 342 522, a formulation for acid-sensitive benzimidazoles is disclosed in which between the alkaline core and the enteric coating is situated an intermediate layer which is composed of an only slightly water-soluble film-forming material, such as ethylcellulose or polyvinyl acetate, and a slightly water-soluble fine-grain inorganic or organic material suspended therein, such as, for example, magnesium oxide, silicon oxide or sucrose fatty acid esters.
EP-A-0 277 741 describes spherical grains or granules having a core which is coated with spray powder which contains low-substituted hydroxypropyl-cellulose and a benzimidazole compound having antiulcer activity. These grains can be coated with an enteric coating agent.
WO96101623, WO96/01624 and WO96/01625 describe an administration form for acid-labile H+/K+ ATPase inhibitors in which active compound pellets together with tablet auxiliaries are compressed to give a tablet. The pellets consist of cores which contain the acid-labile H+/K+ ATPase inhibitor together with alkaline compounds or as an alkaline salt. The cores of the pellets are coated with one or more layers, at least one layer having enteric properties. The enteric layer must in this case be mechanically constituted such that on compression to give tablets the acid resistance of the pellets is not adversely affected. It is mentioned that the preparation of the cores of the pellets can be effected by spray drying.
WO97125030 describes the processing of the abovementioned pellets to give an effervescent tablet.
As the abovementioned prior art shows, the preparation of oral administration forms for acid-labile active compounds requires technically complicated processes.